This application is a 371 of PCT/JP99/04264 filed Aug. 6, 1999.
The present invention relates to a therapeutic or preventive agent for, among other epilepsies, intractable epilepsies, which are difficult to prevent or treat by existing antiepileptics.
Epilepsy is a chronic brain disease in which epileptic seizures are the predominant feature. Generally, most epilepsies and diseases associated therewith are difficult to treat, since epilepsies are not etiologically elucidated. Thus, administration of an antiepileptic agent is a common approach toward suppressing epileptic seizures or inhibiting propagation of focal seizures to other portions.
At present, more than ten types of antiepileptic agents are available in Japan. Yet, many different intractable epilepsies cannot be successfully suppressed by antiepileptic agents, including so-called xe2x80x9cresistant-to-therapyxe2x80x9d seizures and cases in which drug compliance cannot be obtained due to side effects despite satisfactory suppression of seizures. Thus, there is still demand for an antiepileptic agent which is more effective than existing ones and which exhibits fewer and less severe side effects (see xe2x80x9cMechanismus of Action Antiepileptics,xe2x80x9d Clinical Psychiatry Courses, Nakayama-Shoten, authored by Akira TAKAZAWA, et al.).
Therefore, an object of the present invention is to provide a pharmaceutical effective for intractable epilepsies or a seizure associated therewith, for which existing antiepileptics have not exhibited satisfactory efficacy.
The present inventors have conducted extensive studies, and have found that a pyrrolidinylalkylcarboxylic acid amide derivative represented by formula (I) serves as a pharmaceutical which is efficacious in the treatment or prevention of intractable epilepsies. The present invention has been accomplished based on this finding.
Accordingly, the present invention provides a therapeutic or preventive agent for an intractable epilepsy or a seizure associated therewith comprising as an active ingredient a compound represented by the following formula (I):
R2xe2x80x94CH2CONHxe2x80x94R1xe2x80x83xe2x80x83(I)
wherein R1 is a phenyl group or a pyridyl group, either of which may have one or more substituents which may be identical to or different from one another and which are selected from among a C1-C3 alkyl group and a hydroxyl group, and R2 is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents, wherein said one or more substituents may be identical to or different from one another and are selected from among a halogen atom, a hydroxyl group, and a C1-C3 alkyl group; a salt thereof; or a hydrate of the compound or the salt.
The present invention also provides an inhibitor which limits a motor seizure associated with an epilepsy (in terms of duration of an epileptic symptom); an inhibitor for propagation of an epileptic seizure; and a therapeutic or preventive agent for epilepsy having a function of raising a seizure-inductive threshold, each of the above three types of agents comprising as an active ingredient a compound represented by the formula (I), a salt thereof, or a hydrate of the compound or salt. The present invention provides use of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt, for producing a therapeutic or preventive agent for an intractable epilepsy or a seizure associated therewith.
The present invention also provides use of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt, for producing a suppresser which limits a motor seizure associated with an epilepsy (in terms of duration of a epileptic symptom); a suppresser for propagation of an epileptic seizure; and a therapeutic or preventive agent for epilepsy having a function of raising a seizure-inductive threshold.
The present invention provides a method for treating an intractable epilepsy or a seizure associated therewith through administration of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt.
The present invention, also provides a method for treatment for inhibiting a motor seizure associated with an epilepsy (in terms of duration of a epileptic symptom); a method for treatment for preventing propagation of an epileptic seizure; and a method for treating epilepsy involving a function of raising a seizure-inductive threshold, by the administration of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt.
The substituents in formula (I) will next be described. R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group, or a substituted phenyl group. Of these, a phenyl group or a substituted phenyl group is preferred as R1. The one or more substituents for a phenyl group may be identical to or different from one another and are selected from among a C1-C3 alkyl group, a halogen atom, and a hydroxyl group. Of these, a methyl group and a hydroxyl group are preferred. Furthermore, two methyl groups or a combination of two methyl group and one hydroxyl group are preferred, and the preferable positions of substitution are 2- and 6-positions of a phenyl group. Thus, a 2,6-dimethylphenyl group is particularly preferred. The one or more substituents for a pyridyl group may be identical to or different from one another and are selected from among a halogen atom, a C1-C3 alkyl group, an acyl group, etc.
R2 is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents. The one or more substituents may be identical to or different from one another and are selected from among a halogen atom, a C1-C3 alkyl group, and a hydroxyl group. Of these, a hydroxy-substituted-2-oxopyrrolidinyl group and 2-oxopyrrolidinyl group are particularly preferred.
A typical example of the compound represented by formula (I) is N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (generic name: nefiracetam), a salt thereof, and a hydrate of the compound or salt.
A process for producing nefiracetam has already been disclosed in Japanese Patent Application Laid-Open (kokai) Nos. 56-2960, 61-280470, and 6-65197.
Nefiracetam finds pharmaceutical use as, for example, a cerebovascular dementia-ameliorating agent (Japanese Patent Application Laid-Open (kokai) No. 56-163145), an ameliorating agent for dementia of Alzheimer type (Japanese Patent Application Laid-Open (kokai) No. 5-163144), or a stabilizing agent for the mitochondrial membrane (Japanese Patent Application No. 8-260649). The working mechanism of nefiracetam is partially disclosed in Japanese Patent Application No. 9-249131.
An antiepileptic action provided by nefiracetam has already investigated through a test employing EL mice as models, and potential use as an antiepileptic agent is indicated (the 17th Convention of Japanese Neuroscience Society, 3i, 1993; the 23rd Society for Neuroscience, 1993, 11; and the 26th Society for Neuroscience, Nov. 16, 1996, Washington D.C.).
The model of epilepsy employing EL mice tested in the above reports is a model of epilepsy caused by a congenital genetic disposition formed through mutation. The model exhibits perception-evoked secondary generalization of a seizure and stupor after tonic or clonic convulsion. An electroencephalogram of the model shows characteristic changes corresponding to the above states. In addition, the model of epilepsy is a genetic model, to thereby serve as a useful model for investigating epileptic states induced by genetic disposition.
However, no clinically defined types of epilepsies of humans correspond to the EL mouse model, although efficacy of a pharmaceutical to suppress epilepsy is easily attained for EL mice through administration of a pharmaceutical in a small dose. Therefore, the pharmaceutical is not always clinically effective for humans even though the efficacy is proven for EL mice. Particularly, since a clinical effect of a pharmaceutical on intractable epilepsy of humans still involves an unknown issue, the model is not suitable for evaluating the prospects of the clinical effect.
In view of the foregoing, the present inventors have conducted earnest studies, and have found that the compound represented by formula (I) suppresses not only a focal seizure but also a secondary generalized seizure in a model of focal epilepsy, which has been difficult to treat by use of a conventional therapeutic agent. Accordingly, an object of the present invention is to provide a suppresser for focal epilepsies; a suppressor for secondary generalization; and a therapeutic or preventive agent for intractable epilepsies.
Thus, the present invention relates to a therapeutic or preventive agent for intractable epilepsies. First, an explanation of xe2x80x9cintractable epilepsyxe2x80x9d will be given below.
The characteristics of intractable epilepsy include 1) high occurrence of partial seizure followed by a generalized seizure (particularly temporal lobe epilepsy); 2) high occurrence of symptomatic epilepsy caused by an organic lesion in the brain; 3) long-term absence of treatment from the onset to consultation of a specialist and high occurrence of seizures; and 4) high occurrence of status epilepticus in the anamnesis. In other words, the temporal lobe is likely to be a portion of the brain responsible for intractable epilepsy. It is indicated that epilepsy becomes more intractable by changing of the nature thereof and evolving as acquired seizures are repeated.
Intractable epilepsy is categorized into three clinical types, i.e., (a) localization-related epilepsies and syndromes, (b) generalized epilepsies and syndromes, and (c) epilepsies and syndromes undetermined, whether focal or generalized.
Examples of (a) localization-related epilepsies and syndromes include temporal lobe epilepsies, frontal lobe epilepsies, and multi-lobe epilepsies. Temporal lobe epilepsies and frontal lobe epilepsies are typical examples of intractable epilepsy. Multi-lobe epilepsies are considered to be caused by two or more lobes.
Examples of (b) generalized epilepsies and syndromes include Lennox-Gastaut syndrome, West syndrome, and myoclonic epilepsy.
Examples of (c) epilepsies and syndromes undetermined, whether focal or generalized, include severe myoclonic epilepsy in infancy, which exhibits a variety of seizure types. In particular, tonic-clonic seizures frequently occur, to thereby often lead to status epilepticus. Thus, special treatment conducted by a specialist for epilepsy is strongly required (Masako WATANABE, et al., Igakuno Ayumi, 183(1):103-108, 1997).
Seizures associated with intractable epilepsy are categorized into a variety of types, e.g., tonic seizures, tonic-clonic seizures, atypical absence seizures, atonic seizures, myoclonic seizures, clonic seizures, simple partial seizures, complex partial seizures, and secondary generalized seizures. Of these, for tonic and atonic seizures, attention must be paid to injuries resulting from falls.
In addition, complex partial seizures may cause a behavior-caused accident during disturbance of consciousness. In intractable epilepsies, xe2x80x9ccomplex partial seizuresxe2x80x9d associated with temporal lobe epilepsies and frontal lobe epilepsies occur at relatively high frequency in adults. Although said seizures occur at low frequency in children, the seizures are also intractable as in the case of adults (Progress of Epileptology, No. 2, Haruo AKIMOTO and Toshio YAMAUCHI, Iwanami Gakujutsu Shuppan, 1991, p 51-85).
In the present description, the term xe2x80x9cintractable epilepsyxe2x80x9d refers to epilepsies or seizures associated therewith corresponding to the following four epilepsies or seizures associated therewith:
(1) epilepsies difficult to treat in which suppression of seizures associated therewith cannot be controlled through a conventional pharmaceutical treatment (Masako WATANABE, et al., Igaku-no Ayumi, 183(1):103-108, 1997);
(2) epilepsies corresponding to the following (a) to (c): (a) localization-related epilepsies such as temporal lobe epilepsis and cortical epilepsis; (b) generalized epilepsies and syndromes such as Lennox-Gastaut syndrome, West syndrome, and myoclonic epilepsy; and (c) epilepsies and syndromes undetermined, whether focal or generalized, such as severe myoclonic epilepsy in infancy;
(3) seizures associated with the above-described intractable epilepsis including tonic seizures, tonic-clonic seizures, atypical absence seizures, atonic seizures, myoclonic seizures, clonic seizures, simple partial seizures, complex partial seizures, and secondary generalized seizures; and
(4) epilepsies such as epilepsies following brain surgery, traumatic epilepsies, and relapsed epilepsies following surgery for epilepsy.
The antiepileptic agent of the present invention is effective for the above four types of intractable epilepsies. Of these, the antiepileptic agent of the present invention is particularly effective for localization-related epilepsies corresponding to (2) (a); seizures such as secondary generalized seizures, complex partial seizures and status epilepticus corresponding to (3) and status epilepticus; and epilepsies following brain surgery, traumatic epilepsies, and relapsed epilepsies following surgery for epilepsy corresponding to (4). The antiepileptic agent of the present invention has a possibly excellent effect to epilepsies such as localization-related epilepsies, temporal lobe epilepsies, and cortical epilepsies.
xe2x80x9cTemporal lobe epilepsy,xe2x80x9d which is one type of intractable epilepsy, will next be described.
Temporal lobe epilepsy is an epilepsy having a seizure focus in the temporal lobe, and is categorized under symptomatic and localization-related epilepsies, which also include frontal lobe epilepsies, parietal lobe epilepsies, and occipital lobe epilepsies, based on the international classification of epilepsy.
The syndromes of temporal lobe epilepsy vary in accordance with a focus-localized site and type of seizure propagation, in that the temporal lobe has an anatomically complex structure including neocortex, allocortex, and paleocortex. Temporal lobe epilepsy, as previously defined as a psychomotor seizure, mostly causes complex partial seizures as clinically observed seizures, and also causes simple partial seizures, secondary generalized seizures, and combinations thereof.
Simple partial seizures include autonomic and mental symptoms and sensory symptoms such as olfaction, audition, or vision, sometimes concomitant with symptoms of experiences such as deja-vu and jamais-vu. Complex partial seizures often exhibit motion stopping followed by eating-function automatism, and are divided into amygdala-hippocampus seizures and lateral temporal lobe seizures according to localization. In the case of temporal lobe epilepsy, 70-80% of the seizures are hippocampus seizures, in which aura, motion stopping, lip automatism, and clouding of consciousness are successively developed to result in amnesia. When the focus is in the amygdala, there are caused autonomic symptoms such as dysphoria in the epigastrium; phobia; and olfactory hallucination. Lateral temporal lobe seizures include auditory illusion, hallucination, and a dreamy state, and disturbance of speech when the focus is in the dominant hemisphere. Temporal lobe epilepsy exhibits a long-term psychosis-like state in addition to other symptoms and recognition-and-memory disorder more frequently than do other epilepsies (Medical Dictionary, Nanzando). Treatment of temporal lobe epilepsy is carried out through pharmacotherapy employing a maximum dose of a combination of drugs, or through surgical treatment.
xe2x80x9cCortex epilepsy,xe2x80x9d which is one type of intractable epilepsy, will next be described. Cortex epilepsy is an epilepsy having a focus in the cerebral cortex, and is classified as symptomatic epilepsy belonging to localization-related (focal) epilepsies and syndromes in the international classification of epilepsy. In the international classification, seizures associated with cortex epilepsy are classified as simple partial seizures, which are partial seizures without reduction of consciousness. Accordingly, an electroencephalogram taken during a seizure associated with cortex epilepsy (not always recorded on the scalp) exhibits localized contralateral electric discharge from the corresponding cortical field. The rate of seizures associated with cortex epilepsy to the entirety of seizures associated with epilepsies is approximately 15%, and about ⅔ thereof are focal motor seizures including Jacksonian seizures (Wada et al.). Cortex epilepsies are mainly caused by cerebral tumor, an aftereffect of cephalotrauma, etc.; or damage during a perinatal period (Medical dictionary, Nanzando). Based on the focus, cortex epilepsy is classified as temporal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy.
xe2x80x9cTraumatic epilepsy,xe2x80x9d which is one type of intractable epilepsy, will next be described.
Traumatic epilepsy, in a broad sense, is divided into two epilepsies, i.e., xe2x80x9cearly epilepsyxe2x80x9d and xe2x80x9clate epilepsy.xe2x80x9d xe2x80x9cEarly epilepsyxe2x80x9d is caused through stimulation of the brain induced by convulsion within a week after suffering a trauma, and is not a true epilepsy. In contrast, xe2x80x9clate epilepsyxe2x80x9d is a true epilepsy that is caused one or more weeks after suffering a trauma. Japan produces 100,000-200,000 candidates for traumatic epilepsy per year (Shinya MANAKA, Kyukyu Iryo, 17:1076-1077).
Most of the traumatic epilepsies are caused by formation of a focus at a traumatically damaged portion of the cortex, and they are considered to be typical examples of partial epilepsies. Therefore, treatment thereof is principally based on a pharmacotherapy which is generally employed for treatment of epilepsy. However, since onset and a process of individual symptoms are diverse, in many cases the epilepsy becomes intractable through administration of an antiepileptic agent, as reported in Nihon Saigai Igakukai Kaishi, 32(6):453-460, 1984. Meanwhile, surgical treatment has been employed for actually existing intractable symptoms in which control of a seizure is difficult (Yoshifumi MATSUMOTO, Neurotraumatology, 17:101-106, 1994). xe2x80x9cA secondary generalized seizure,xe2x80x9d which is one of the symptoms associated with intractable epilepsy, will next be described.
The secondary generalized seizure is one type of partial seizure, which exhibit a clinical syndrome and an electrocephalogram feature observed as excitation of neurons that shows initiation of a seizure in a limited portion of one cerebral hemisphere.
The secondary generalized seizure is initiated as a simple partial seizure (without impairment of consciousness) or a complex partial seizure (with impairment of consciousness), and develops to general convulsion induced through secondary generalization. The main symptom thereof is convulsion such as a tonic-clonic seizure, a tonic seizure, or a clonic seizure (Kazuyoshi WATANABE, the 22th Nou-no Igaku Seibutsugaku Kenkyuukai, 1997. 1. 18).
xe2x80x9cA complex partial seizure,xe2x80x9d which is one of the symptoms associated with intractable epilepsy, will next be described.
The complex partial seizure refers to a partial seizure with impairment of consciousness, and is similar to a seizure that has conventionally been called a psycho-motor seizure or a seizure associated with temporal lobe epilepsy. In the international classification draft (1981), the complex partial seizure is defined as a seizure xe2x80x9cwith impairment of consciousness exhibiting an electrocephalogram during a seizure in which unilateral or bilateral electric discharge attributed to a focus in a diffuse or a temporal or front-temporal portion.xe2x80x9d
Actually, the neuromechanism responsible for the above type of seizures is considered to include the amygdala, the hippocampus, the hypothalamus, the parolfactory cortex, etc., in addition to the frontal and temporal lobes. The seizures typically last 1-2 minutes or slightly longer, and the onset and cessation of the seizures are not abrupt but gradual. Examples of complex partial seizures include (1) seizures with reduction of consciousness (gradually evolving impairment of consciousness, arrest of motion, speech, and reaction, and amnesia); (2) cognitive seizures (deja-vu, jamais-vu, ideo-seizures); (3) affective seizures (fear, anger, emptiness, strangeness, delight, joy); (4) psycho-sensory seizures (hallucinations; visual, auditory, gustatory, olfactory, cenesthesia); and (5) psycho-motor seizures (automatism, lip-licking, chewing, stereotypy). The onset of the seizures can be observed, mainly at the age of 10-25, but at any age (Epilepsy, Nihon Bunkakagaku-sha, 49-51, 1996, edited by Haruo AKIMOTO).
xe2x80x9cStatus epilepticus,xe2x80x9d which is one type of intractable epilepsy, will next be described.
In status epilepticus, consciousness is not restorable during a seizure associated with epilepsy that lasts for 30 minutes or longer or repeats. Any type of seizure may evolve to status epilepicus. The most common case is a tonic-clonic seizure, and status epilepticus thereof is fatal and must be treated immediately. In many cases, cessation of an antiepileptic agent induces status epilepticus. Thus, an atilepitic agent is administered intravenously while the central nervous system disorder and whole-body conditions are monitored and controlled, and elucidation of the cause and treatment thereof is progressing (Nanzando, Medical Dictionary). Since a status epilepticus convulsion is known to cause intractable epilepsy, immediate and appropriate action is required for the diagnosis of and first aid for a status epilepticus convulsion. Suppression of a convulsive seizure at the early stage is an important key to aftercare (Teruyuki OGAWA, Clinical Pediatrics; 47(12):2673-2681. 1994).
Clinical models for intractable epilepsy of humans are produced by use of animals. Example of such animal models include a xe2x80x9ckindling modelxe2x80x9d and a xe2x80x9cSeizures induced by kainic acid.xe2x80x9d
The xe2x80x9ckindling modelxe2x80x9d serving as a model for intractable epilepsy will be described. When weak electrical stimulation is applied to a certain portion in the brain repeatedly at intervals, evolution of a partial seizure to a generalized seizure is observed. This phenomenon is called kindling. Epileptic origin is formed in the brain while kindling lasts for a long time after cessation of stimulation and sometimes causes a spontaneous epileptic seizure. Although kindling is a long-term phenomenon, no large-scale morphological change of the brain is found. Thus, the kindling model serves as a typical experimental model for epilepsy in that non-specific epileptic origin involving no tissue damage is acquired in the brain and persists for a long time. By use of such a model, a potentiation process of acquired epileptic origin relating to intractable epilepsy can be investigated, and research can be performed for pathologically specific stages such as onset, continuation, and cessation of seizures; a post-seizure stage; and a seizure-absence stage (Mitsumoto SATO, the 22th Igaku Seibutsugaku Kenkyuukai, resume of lectures, 1997. 1. 18).
A variety of models for epilepsy can be produced from a kindling model, in that a stimulation portion is selectable. The most sensitive portion is the amygdala, which is repeatedly stimulated at a afterdischarge threshold (minimum stimulation intensity) (in general, once per day), to exhibit seizure stages as follows: Stage 1 (chewing); Stage 2 (head nodding); Stage 3 (forelimb clonus); Stage 4 (rearing); and Stage 5 (rearing and falling). Stages 1 and 2 correspond to a complex partial seizure of human temporal lobe epilepsy, and Stages 3 to 5 are considered to be stages of secondary generalized seizure. Stage 5 is regarded as a stage of establishment of kindling. Once kindling is established, susceptibility to electrical stimulation is maintained almost for life.
Kindling is similar to human epilepsy not only in terms of seizure symptoms but also in evaluation of an effect of an antiepileptic agent and the like. Thus, kindling is useful means for understanding of epileptic phenomena. By use of a kindling model having a focus in the limbic system or the cortex, a variety of phenomena can be assured; e.g., an effect on a partial seizure; an effect on an development stage from a partial seizure to a secondary generalized seizure; action mechanisms thereof (such as action for acquisition of epileptogenesis, and neuromechanism relating to generalization of a seizure in the limbic system); and an effect on clinical symptoms. A pharmaceutical effect during a kindling development process toward establishment of a generalized seizure is called xe2x80x9cpreventive effect,xe2x80x9d which is evaluated by a preventive effect of a pharmaceutical on acquisition of epileptogenesis. A pharmaceutical effect during a kindling development process involving repeated stimulation after establishment of a generalized seizure is called xe2x80x9ctherapeutic effectxe2x80x9d (Juhn. A. Wada; Mitsumoto SATO, and Kiyoshi MORIMOTO, Neuroscientific Mechanism of Epilepsy Studied with a Kindling Model, p 225-241, 1993). Thus, a kindling model is known as an excellent animal model for the treatment-resistent tempolal lobe epilepsy with a complex partial seizure, a secondary generalized seizure of human.
The present inventors have studied the effects of nefiracetam on an development process of the amygdaloid kindled seizures and on establishment of kindling through a method described below, and have determined the efficacy of nefiracetam. The evolution process of kindling is tested by use of rats, in which electrodes are placed in the amygdala and kindling stimulation (50 Hz sine wave, duration of 1 second, once per day) is applied at specific intervals for restoration. On the first day, an afterdischarge-provocation threshold is determined without administration of a pharmaceutical. From the second day, kindling stimulation having intensity of the afterdischarge-provocative threshold is applied to rats administered with a specimen at a variety of administration doses, to thereby investigate an effect of the specimen on the evolution process of kindling.
Use of nefiracetam as a specimen under such conditions enabled investigation of the effect of nefiracetam on parameters such as a seizure stage and afterdischarge duration on a stimulated side of the amygdala during seizure propagation of amygdala kindling.
The results of such investigation revealed that a group of rats to which nefiracetam had been administered in an amount of 180 mg/kg include a number of rats which do not reach Stage 5 even though the afterdischarge duration is extended, and that a group of rats to which nefiracetam had been administered in an amount of 90 mg/kg exhibit inhibition of stable induction of Stage 5. Although typically the xe2x80x9cafterdischarge thresholdxe2x80x9d is expected to decrease with evolution of kindling, remarkably, approximately half of rats to which nefiracetam had been administered in an amount of 90 mg/kg exhibited a sudden increase in afterdischarge threshold in a process from Stage 3 to Stage 5.
Next, the effects of nefiracetam on a establishment of the amygdala kindled seizures were investigated with regard to the seizure stage, afterdischarge duration, and motor seizure duration, as follows. In order to further clarify the response to the pharmaceutical, the kindling stimulation intensity was used as 1-3 times that of generalized seizure threshold (GST) where Stage 5 is constantly developed.
The results of such investigation revealed that administration of nefiracetam (120 mg/kg) exhibits a strong and significant suppression effect on all parameters under the stimulation intensity equivalent to GST. In the case of a group of rats stimulated at an intensity equivalent to 2-times-GST, a parameter relating to the afterdischarge duration was restored to a value of the non-administration level, and the seizure stage and the motor seizure duration were significantly suppressed. In the case of a group of rats stimulated at an intensity equivalent to 3-times-GST, the afterdischarge duration was restored, and a tendency toward restoration of the seizure stage and the motor seizure duration was proven.
As described above, the effects of nefiracetam depend on the stimulation intensity. Therefore, the effect on suppression of a kindling seizure is indicated to involve two factors; i.e., increase of the afterdischarge threshold at a seizure-inducing portion and suppression of seizure spreading to the entirety of the brain.
An antiepileptic action of the compound represented by formula (I) was investigated by use of another model, the xe2x80x9cSeizures induced by kainic acid (kainate model),xe2x80x9d serving as a model for intractable epilepsy. The kainate model is an epileptic model in which kainic acid, which is one of the excitatory amino acids found in the brain, is injected to nuclei (amygdala, hippocampus, etc.) in the limbic system in an microamount to thereby induce focal epilepsy. The kainate model serves as a model for an epileptic seizure; more particularly, as a model for status epilepticus induced from the limbic system in an acute phase, and as a model for evolution of a spontaneous limbic seizure to a secondary generalized seizure in a chronic phase. Thus, the kainate model is recognized as a model for intractable epilepsy. In addition, the model is also employed as a model for intractable human temporal lobe epilepsy in that the model satisfies the following conditions: (a) existence of a focus of epilepsy in tissue (amygdala, hippocampus, etc.) in the limbic system; (b) change in tissue equivalent to hardening of the hippocampus; (c) repeated and continual development of spontaneous complex partial seizure (limbic system seizure); and (d) no therapeutic effect provided by a customary pharmaceutical (edited by Tatsuya TANAKA, Frontier of Epileptic Research, p 14, 1994, 1st Japan Winter Conference on Brain Research, Life-Science Publishing). The kainate model may also be used as a cortex epilepsy model through injection of kainic acid to the cortex (sensorymotor field). Furthermore, since local blood flow increases during a epileptic seizure, the correlation between glucose metabolism during status epilepticus of the limbic system and local brain blood flow can be investigated through autoradiography by use of the model, and an effect of the epileptic seizure on a damage of cells can also be investigated.
Although the mechanism of the seizure development in the kainate model is not completely elucidated, the following mechanism is proposed. That is, a proposed mechanism comprises (a) continuation of epileptic stimulation induced by anomalous accumulation of glutamate due to bonding of kainate to glutamate-receptors; (b) synergism of kainate and glutamate released from presynaptic terminals; and (c) release of a toxic amount of glutamate or aspartate due to stimulation by kainate-receptors contained in presynapses (edited by Tatsuya TANAKA, Frontier of Epileptic Research, p18, 1994, 1st Japan Winter Conference on Brain Research, Life-Science Publishing).
In connection with clinical epileptic symptoms, the kinate model corresponds to a model for intractable temporal lobe epilepsy (injection to the amygdala or hippocampus) and to a model for intractable cortex epilepsy (injection to the sensorymotor field (Tatsuya TANAKA, BIO Clinica, 11(9), 695-697).
The excellent antiepileptic action of nefiracetam is proven through injection thereof to rats of the kainate model, one of the intractable epilepsy models. A high dose of nefiracetam clinically suppressed both a kainate-induced amygdala seizure and a cortex focal seizure, and the suppression was observed in an electrocephalogram. The degree of suppression is stronger in relation to a cortex focal seizure. The identical kainate model, proves that administration of nefiracetam suppresses hypermetabolism in the brain and propagation of a seizure from a focus. The suppression effect is stronger in the cortex. Since nefiracetam dose-dependently suppressed propagation of seizure related-hypermetabolism, the seizure-suppression mechanism of nefiracetam is based on suppression of seizure propagation. Furthermore, the above action corresponds to a suppression action of brain glucose metabolism predominantly in the cortex, in that nefiracetam exhibits a sedative action to rats.
Kainic acid, a strong neuroexitatory amino acid, is well known to induce a convulsive seizure through systemic administration or local administration in the brain. Injection of kainic acid in a microamount to one side of the amygdaloid of an animal such as a cat or rat induces status epilepticus of limbic system epilepsy in an acute phase and a spontaneous limbic system seizure in a chronic phase, to thereby realize a model for epilepsy similar to human temporal lobe epilepsy. The status epilepticus of a kainate-induced amygdala seizure in an acute phase is very severe, and only a high concentration of zonisamide among known antiepileptic agents has a proven suppression effect. Nefiracetam exhibited a suppression effect on a kainate-induced amygdala seizure in a dose as high as 200 mg/kg. However, the suppression effect was temporary and lasted for some minutes or some hours, and a seizure appeared again. Meanwhile, nefiracetam exhibited a remarkable suppression effect on a kainate-induced cortex focal seizure for all tested rats through administration in an amount of 100 mg/kg, and seizure suppression was maintained from immediately after administration of nefiracetam such that seizure never appeared again. Thus, nefiracetam was revealed to exhibit a suppression effect on both a kainate-induced amygdala seizure and a kainate-induced cortex focal seizure, and the suppression effect was revealed to be stronger to a cortex focal seizure.
In addition, in both models, nefiracetam was intravenously injected to rats to provide sedation, and algodiapholia and chalasia of quarters were observed. This indicated that nefiracetam suppresses functions of the entire cortex. Furthermore, the investigation with regard to the change in local glucose metabolism during a seizure revealed that administration of nefiracetam in an amount of 100 mg/kg lowers glucose metabolism throughout the entire brain in both the case of an amygdala seizure and the case of a cortex focal seizure. Particularly, glucose metabolism was lowered to below a normal level in portions of the cortex and the basal ganglia on the non-focal side. When the dose of nefiracetam increased, evolution of a hypermetabolism domain with seizure propagation was suppressed dose-dependently. A hypermetabolism domain was limited at a focus in the amygdala through administration at. 200 mg/kg. Such effects on glucose metabolism during a seizure indicate that nefiracetam suppresses propagation of a seizure. In addition, strong suppression of cerebral glucose metabolism and the basal ganglia indicates that nefiracetam is more effective in relation to a cortex focal seizure than in relation to a limbic system seizure, as shown in the observation of an electrocephlogram. A sedative action of nefiracetam at high concentration is considered to be attributed to affinity thereof to the cortex.
The manner of administration of the antiepileptic agents for intractable epilepsies of the present invention is not particularly limited, and the agents may be administered to humans perorally or parenterally. The above-described compound represented by formula (I), an active ingredient of the pharmaceuticals of the present invention, may be administered directly. However, typically, a pharmaceutical composition which is prepared by use of the compound represented by formula (I) and one or more pharmaceutically acceptable additives is preferably administered perorally or parenterally.
The dose of the pharmaceutical of the present invention is not particularly limited, and is appropriately selected in accordance with the manner of administration, severity of a symptom of epilepsy or seizures, frequency of seizures, object of administration, e.g., preventive or therapeutic, and age or weight of the patient. For example, the daily dose of the compound represented by formula (I) for an adult is 200-2,000 mg, preferably about 300-900 mg, and the daily dose may be divided. The timing of administration of the pharmaceutical of the present invention may also be appropriately selected. If the pharmaceutical is administered before onset of epileptic symptoms or seizures, it serves as an antiepileptic agent.
Examples of the form of formulation suitable for peroral administration include tablets, capsules, powders, granules, liquids, and syrups. Examples of the form of formulation suitable for parenteral administration include subcutaneous, intravenous, and intramuscular injections; drips; inhalants; percutaneous or premucosa absorption formulations; suppositories; and cataplasmas. Examples of pharmaceutically acceptable additives include excipients, disintegrators, disintegration aids, binders, lubricants, coatings, colorants, diluents, bases, solubilizers or solubilization aids, isotonic agents, pH-adjusters, propellants, and stickers.
For example, pharmaceutically acceptable additives may be incorporated into formulations suitable for peroral administration and percutaneous or permucosa administration. Examples of the additives include excipients such as glucose, D-mannitol, starch, and cryslalline cellulose; disintegrators or disintegration aids such as calcium carboxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gelatin; lubricants such as magnesium stearate and talc; coatings such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, and titanium oxide; and bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat.
Furthermore, the formulations may be produced through incorporation of propellants such as Fron, diethyl ether, and compressed gas; stickers such as sodium polyacrylate, polyvinyl alcohol, methylcellulose, polyisobutylene, and polybutene; and base cloths such as cotton cloth and plastic sheets. Additives for formulation may be incorporated into formulations suitable for injections and drips, e.g., solubilizers or solubilization aids which serve as a component of injections which are aqueous or must be made soluble before use. Examples thereof include distilled water for injection, sodium chloride for injection, and propylene glycol. There may also be added isotonic agents such as glucose, sodium chloride, D-mannitol, and glycerin and pH-regulators such as inorganic and organic acids and inorganic and organic bases.
Nefiracetam, a typical pharmaceutical of the present invention, has an acute toxicity of 2,005 mg/kg (male mouse, peroral) and therefore, is highly safe (Japanese Patent Application Laid-Open (kokai) No. 5-163144).